Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet factor 4

Mònica Arman,Krystin Krauel,Dorothea O Tilley,Claudia Weber,Dermot Cox,Andreas Greinacher,Steven W Kerrigan,Steve P Watson

doi:10.1182/blood-2013-11-540526

Abstract

AbstractBacterial adhesion to platelets is mediated via a range of strain-specific bacterial surface proteins that bind to a variety of platelet receptors. It is unclear how these interactions lead to platelet activation. We demonstrate a critical role for the immune receptor FcγRIIA, αIIbβ3, and Src and Syk tyrosine kinases in platelet activation by Staphylococcus aureus, Streptococcus sanguinis, Streptococcus gordonii, Streptococcus oralis, and Streptococcus pneumoniae. FcγRIIA activation is dependent on immunoglobulin G (IgG) and αIIbβ3 engagement. Moreover, feedback agonists adenosine 5′-diphosphate and thromboxane A2 are mandatory for platelet aggregation. Additionally, platelet factor 4 (PF4) binds to bacteria and reduces the lag time for aggregation, and gray platelet syndrome α-granule–deficient platelets do not aggregate to 4 of 5 bacterial strains. We propose that FcγRIIA-mediated activation is a common response mechanism used against a wide range of bacteria, and that release of secondary mediators and PF4 serve as a positive feedback mechanism for activation through an IgG-dependent pathway.

Highlights

Despite an increasingly recognized role for platelets in immunity,[1,2,3,4] our knowledge of the molecular events that control platelet-bacteria interactions is rudimentary
This is in contrast to the immediate onset and partial response induced by cross-linking of an intermediate concentration of monoclonal antibody (mAb) IV.[3] to induce clustering of FcgRIIA,[37] with full aggregation observed in response to a higher concentration
Aggregation was associated with robust secretion of dense and a-granules as shown by measurement of Adenosine triphosphate (ATP) and platelet factor 4 (PF4), respectively, which is similar in magnitude to that induced by FcgRIIA clustering (Figure 1B-C)

Summary

Introduction

Despite an increasingly recognized role for platelets in immunity,[1,2,3,4] our knowledge of the molecular events that control platelet-bacteria interactions is rudimentary. Infective endocarditis is a focal infection of the heart valves characterized by inflammation that is associated with the build-up of platelets, fibrin, and bacteria on the valves of the heart.[10] The biggest risk for patients is embolization of the clots to the brain, causing multiple small infarcts. Another life-threatening disease is sepsis, which can lead to sepsis-associated disseminated coagulopathy during which clotting factors are consumed by disseminated microvascular thrombosis. Strains of these species have been shown to stimulate platelet aggregation and secretion directly.[13,14,15,16,17]

Methods

Results

Conclusion